bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, September 5th, 2024
| Time |
Event |
| 9:15a |
Modeling disorders of consciousness at the patient level reveals the network's influence on the diagnosis vs the local node parameters role in prognosis
The study of disorders of consciousness (DoC) is very complex because patients are suffering from a wide variety of lesions, affected brain mechanisms, different symptom severity and are unable to communicate. Combining neuroimaging data and mathematical modeling can help us quantify and better describe some of these alterations. This study's goal is to provide a novel analysis and modeling pipeline for fMRI data leading to new diagnosis and prognosis biomarkers at the individual patient level. To do so, we project patient's fMRI data into a low dimension latent-space. We define the latent space's dimension as the smallest dimension able to maintain the complexity, non-linearities, and information carried by the data, according to different criteria that we detail in the first part. This dimensionality reduction procedure then allows us to build biologically inspired latent whole-brain models that can be calibrated at the single-patient level. In particular, we propose a new model inspired by the astrocyte regulation of neuronal activity in the brain. This modeling procedure leads to two types of model-based biomarkers (MBBs) that provide novel insight at different levels: (1) the connectivity matrices bring us information about the severity of the patient's diagnosis, and, (2) the local node parameters, correlate to the patient's etiology, age and prognosis. | | 10:32a |
Brain-wide circuitry underlying altered auditory habituation in zebrafish models of autism.
Auditory processing is widely understood to occur differently in autism, though the patterns of brain activity underlying these differences are not well understood. The diversity of autism also means brain-wide networks may change in various ways to produce similar behavioral outputs. We used larval zebrafish to investigate auditory habituation in four genetic lines relevant to autism: fmr1, mecp2, scn1lab and cntnap2. In free-swimming behavioral tests, we found each line had a unique profile of auditory hypersensitivity and/or delayed habituation. Combining the optical transparency of larval zebrafish with genetically encoded calcium indicators and light-sheet microscopy, we then observed brain-wide activity at cellular resolution during auditory habituation. As with behavior, each line showed unique alterations in brain-wide spontaneous activity, auditory processing, and adaptation in response to repetitive acoustic stimuli. We also observed commonalities in activity across our genetic lines that indicate shared circuit changes underlying certain aspects of their behavioral phenotypes. These were predominantly in regions involved in sensory integration and sensorimotor gating rather than primary auditory areas. Overlapping phenotypes include differences in the activity and functional connectivity of the telencephalon, thalamus, dopaminergic regions, and the locus coeruleus, and excitatory/inhibitory imbalance in the cerebellum. Unique phenotypes include loss of activity in the habenula in scn1lab, increased activity in auditory regions in fmr1, and differences in network activity over time in mecp2 and cntnap2. Comparing these distinct but overlapping brain-wide auditory networks furthers our understanding of how diverse genetic factors can produce similar behavioral effects through a range of circuit- and network-scale mechanisms. | | 10:32a |
Developmental changes in hippocampal neurite colocalize with the expression of genes involved in modulating low-theta oscillations
The hippocampus is a critical brain structure that supports the encoding and retrieval of episodic memories, yet the intricate development of its microstructure in humans remains unknown. Understanding this microstructural maturation and how it relates with the maturation of hippocampal function may provide critical insight into the basic mechanisms underlying memory and their disruption in disease. To address this gap, we non-invasively estimated the density and branching complexity of neurite (dendrites, axons, glial processes) using diffusion-weighted MRI in 364 participants aged 8-21. We found that these microstructural measures differ between subfields and along the longitudinal axis of the hippocampus. Notably, we observed spatially heterogeneous increases in the branching complexity of neurite until approximately 15 years of age, with prominence in CA1, stratum radiatum/lacunosum/moleculare, subiculum, and the anterior hippocampus. Furthermore, our imaging transcriptomics analysis shed light on the molecular underpinnings of these developmental dynamics. Regions exhibiting substantial age-related increases in neurite orientation dispersion also tend to express genes associated with the modulation of low-theta oscillations during memory encoding. These results suggest that the protracted maturation of hippocampal microstructure may be linked to the development of low-theta oscillation modulations during encoding. | | 10:32a |
Right Caudate Volume and Executive Functions in Children with Attention-Deficit/Hyperactivity Disorder (ADHD)
Background. The caudate and putamen have previously been implicated in Attention-Deficit/Hyperactivity Disorder (ADHD). However, previous studies have not investigated the relationship between the caudate and putamen with executive function (EF). The current study investigated the clinical relevance of the caudate and putamen with respect to EF. Method. We studied 49 children (24 ADHD/25 typically developing children (TDC)). All participants in the ADHD group had to undergo a 48-hour stimulant medication washout period. Participants completed cognitive tasks related to working memory/inhibition and underwent a T1-weighted MRI sequence. All parents completed behaviour rating scales using the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2). Data were analyzed using multivariate analysis of covariance, Pearson correlations, and linear regressions. Results. Children with ADHD demonstrated a higher frequency of perseverative errors compared to TDC (p <.05), and their parents reported significantly more EF challenges (p <.001). No difference was observed in the working memory tasks. No significant volumetric differences were seen in the caudate or the putamen. A linear regression model suggested that the right caudate volume accounted for 10.3% of the variance in emotion regulation as reported by parents on the BRIEF-2 in the overall sample. Discussion. We observed significant EF challenges without volumetric differences. However, the right caudate was correlated to parent ratings of emotional regulation, highlighting the need to consider emotional regulation difficulties in ADHD. | | 10:32a |
Spike frequency adaptation in primate lateral prefrontal cortex neurons results from interplay between intrinsic properties and circuit dynamics
Recordings of cortical neurons isolated from brain slices and dissociated from their networks, display intrinsic spike frequency adaptation (I-SFA) to a constant current input. Interestingly, extracellular recordings in behaving subjects also show extrinsic-SFA (E-SFA) in response to sustained visual stimulation. Because neurons are isolated from brain networks in slice recordings, it is challenging to infer how I-SFA contributes to E-SFA in interconnected brains during behavior. To investigate this, we recorded responses of macaque lateral prefrontal cortex neurons in vivo during a visually guided saccade task and in acute brain slices in vitro. Broad spiking (BS) putative pyramidal cells and narrow spiking (NS) putative inhibitory interneurons exhibited E-SFA in vivo. In acute brain slices, both cell types displayed I-SFA though their magnitudes differed. To investigate how in vitro I-SFA contributes to in vivo E-SFA, we developed a data-driven hybrid circuit model in which local NS neurons are driven by BS input. We observed that model NS cell responses show longer SFA than observed in vivo. Introducing inhibition of NS cells to the model circuit removed this discrepancy. Our results indicate that both I-SFA and inhibitory circuit dynamics contribute to E-SFA in LPFC neurons. They highlight the contribution of single neuron and network dependent computations to neural activity underlying behavior. | | 10:32a |
A conserved cell-type gradient across the human mediodorsal and paraventricular thalamus
The mediodorsal thalamus (MD) and adjacent midline nuclei are important for cognition and mental illness, but their cellular composition is not well defined. Using single-nucleus and spatial transcriptomics, we identified a conserved excitatory neuron gradient, with distinct spatial mapping of individual clusters. One end of the gradient was expanded in human MD compared to mice, which may be related to the expansion of granular prefrontal cortex in hominids. Moreover, neurons preferentially mapping onto the parvocellular division MD were associated with genetic risk for schizophrenia and bipolar disorder. Midbrain-derived inhibitory interneurons were enriched in human MD and implicated in genetic risk for major depressive disorder. | | 11:46a |
Prenatal exposure to valproic acid induces sex-specific alterations in cortical and hippocampal neuronal structure and function in rats
Background: There are substantial differences in the characteristics of males and females with an autism spectrum disorder (ASD), yet there is little knowledge surrounding the mechanistic underpinnings of these differences. The valproic acid (VPA) rodent model is the most widely used model for the study of idiopathic ASD, but almost all of the studies have used male rodents. Method: To fill this knowledge gap, we evaluated sex differences for neuronal activity, morphology, and glycogen synthase kinase-3 (GSK-3) signaling in primary cortical (CTX) and hippocampal (HIP) neurons prepared from rats exposed to VPA in utero. In vivo, sex-specific VPA-induced alterations in the frontal CTX transcriptome at birth were also determined. Results: Overall, VPA induced more robust changes in neuronal function and structure in the CTX than in the HIP. Male- and female-derived primary CTX neurons from rats exposed to prenatal VPA had elevated activity and showed more disorganized firing. In the HIP, only the female VPA neurons showed elevated firing, while the male VPA neurons exhibited disorganized activity. Dendritic arborization of CTX neurons from VPA rats was less complex in both sexes, though this was more pronounced in the females. Conversely, both female and male HIP neurons from VPA rats showed elevated complexity distal to the soma. Female VPA CTX neurons also had an elevated number of dendritic spines. The relative activity of the and {beta} isoforms of GSK-3 were suppressed in both female and male VPA CTX neurons, with no changes in the HIP neurons. On postnatal day 0, alterations in CTX genes associated with neuropeptides (e.g., penk, pdyn) and receptors (e.g., drd1, adora2a) were seen in both sexes, though they were downregulated in females and upregulated in males. Limitations: Primary neuron studies may not recapitulate findings performed in vivo or at later stages of development. Conclusion: Together these findings suggest that substantial sex differences in neuronal structure and function in the VPA model may have relevance to the reported sex differences in idiopathic ASD. | | 1:47p |
Arc/Arg3.1 binds the nuclear polyadenylate-binding protein RRM and regulates neuronal activity-dependent formation of nuclear speckles
Arc is a neuronal activity-induced protein interaction hub with critical roles in synaptic plasticity and memory. Arc localizes to synapses and the nucleus, but its nuclear functions are little known. We show that Arc accumulates in the interchromatin space of dentate granule cell nuclei and the nucleosol subcellular fraction following seizure activity and in vivo dentate gyrus LTP. Proteomic analysis of affinity-purified Arc complexes identified proteins with functions in post-transcriptional mRNA processing. During LTP, Arc undergoes enhanced complex formation with polyadenylate binding protein nuclear 1 (PABPN1) and paraspeckle splicing factor (PSF) in the nucleosol. In vitro peptide binding arrays show selective binding of Arc to the PABPN1 polyA RNA recognition motif. In hippocampal neuronal cultures, Arc knockdown increases formation of PABPN1 nuclear speckles and blocks chemical-LTP associated increases in small PABPN1 foci. These results implicate Arc in basal and neuronal activity-dependent regulation of PABPN1 speckles involved in mRNA processing and polyadenylation. | | 8:17p |
Satellite glial cells modulate proprioceptive neuron activity in dorsal root ganglia
Proprioception, the sense of body and limb position, is mediated by proprioceptors and is crucial for important motor functions such as standing and walking. Proprioceptor cell bodies reside within the peripheral dorsal root ganglia (DRG) and are tightly enveloped by satellite glial cells (SGCs). SCGs express a number of Gq protein-coupled receptors (Gq GPCRs), but their functional consequences on proprioceptor activity is unknown. Using a combination of chemogenetics, genetics, Ca2+ imaging, pharmacology, immunohistochemistry, and biochemistry, we provide evidence that SGC Gq GPCR signaling is sufficient to drive purinergic receptor-mediated Ca2+ responses in proprioceptor cell bodies. Our findings suggest a potential role for SGC Gq GPCR signaling in shaping proprioceptor information processing. Furthermore, this demonstration of SGC-induced proprioceptor activation has profound implications with SGC Gq GPCR signaling and purinergic receptors representing potential therapeutic targets for alleviating some proprioceptor and sensorimotor impairments associated with spinal muscular atrophy or Friedreich's ataxia. | | 8:17p |
The Aquaporin-4 expression and localization in the olfactory epithelium modulate the odorant-evoked responses and olfactory driven behavior
Aquaporin-4 (AQP4) is a water-selective channel expressed in glial cells throughout the central nervous system. It serves as the main water channel in the neuropil, and is involved in various physiological functions, ranging from regulating water homeostasis by adjusting cell volume to modulating neuronal activity. Different isoforms of AQP4 are expressed in glial-like cells known as sustentacular cells (SUSs) of the olfactory epithelium (OE). Interestingly, mice lacking all AQP4 isoforms exhibit impaired olfactory abilities. Hence, we aim to uncover the physiological role of two AQP4 isoforms, the perivascular AQP4ex isoform and the Orthogonal Array of Particle (OAP)-forming isoform (AQP4M23) in the OE. Primarily, we investigated the impact of AQP4 isoforms on OE protein expression, finding reduced levels of mature olfactory sensory neurons (OSNs) in mice lacking AQP4ex (AQP4ex-KO) or OAPs (OAP-null). Moreover, the reduced number of OSNs, SUSs, and globose basal cells (GBCs) suggests that AQP4 isoforms are involved in maintaining an optimal microenvironment in the OE, preserving the overall cell density. Then, we explored the role of AQP4 in modulating odorant-evoked responses through electro-olfactogram recordings, finding reduced odorant responses in mice lacking AQP4 isoforms. Olfactory ability assessments revealed deficits in odor-guided food-seeking test in AQP4ex-KO and OAP-null mice. Furthermore, AQP4ex-KO mice showed a reduced ability to discriminate between different odorants, while OAP-null mice were unable to recognize them as distinct. Overall, our data highlight the role of AQP4 isoforms in modulating neuronal homeostasis, affecting odorant-evoked responses and cell density in the OE. These results shed light on SUSs involvement in mediating these processes and establish a foundation for further understanding their role in controlling OE physiology. |
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